Introduction to the use of Mitomycin C in ophthalmology was a significant development in the 1960s. Its use and application in ophthalmology has been increasing in recent years, because of its modulatory effects on wound healing. Current applications of this drug in ophthalmology include pterygium surgery, glaucoma surgery, corneal refractive surgery, cicatricial eye disease, conjunctival neoplasia, dacryocystorhinostomy surgeries, squint surgeries, and allergic eye disease. Although it has been used successfully in these conditions, it has also been associated with significant complications. This article reviews the current trends and uses of mitomycin C in the eye and its reported complications.

Mitomycin C is an antineoplastic / antibiotic agent isolated from the soil bacterium Streptomyces caespitosus. The drug is also referred to as Mitomycin C, to differentiate it from Mitomycin A and B, which under certain conditions are also produced by Streptomyces caespitosus.

Mitomycin-C, first found its way into ophthalmic use in 1969, in Japan, where recurrent pterygia were successfully treated with the drug. [1]

Clinical pharmacology and mechanism of action

It is an anti-metabolite with anti-proliferative effect on cells showing the highest rate of mitosis by inhibiting DNA synthesis. The chemical formula is C 15 H 18 N 4 O 5[Figure 1]. Reduction in quinine and loss of the methoxy group within the cell converts Mitomycin-C into a bifunctional or trifunctional alkylating agent. Deoxyribonucleic acid (DNA) is inhibited by cross-linking at the N position of Adenine and at 06 and N position of Guanine. The cell cycle is most affected during the late G-I and early S-phase. [2]

Mitomycin is delivered to the eye in a complete solubilized form, often in the presence of conjunctival and corneal epithelial defects, the drug is highly bioavailable to the target tissue. Its hydrophobic character favors its penetration into the epithelially denuded cornea and conjunctiva, while deterring its movements into or through the intact epithelium. [1] The use of Mitomycin eye drops, even at the highest dose used, does not result in any detectable levels of Mitomycin in the blood.

Clinical uses

Mitomycin-C should be reconstituted in sterile water at neutral pH, the drug is inactivated in an acidic solution. The drug should be stored under refrigeration to preserve its potency under these conditions, Mitomycin-C is potent for a period of two weeks.

The following are the day-to-day uses of Mitomycin C in ophthalmological practice:

Uses of mitomycin C in ophthalmolgy

Ocular surface tumors

Pterygium surgery

Dacryocystorhinostomy

Squint surgeries

Refractive surgeries

Allergic conjunctivitis

Mitomycin C in ocular surface tumours

Ocular surface tumors include a variety of neoplasms originating from the squamous epithelium, melanocytes, and lymphocytic resident cells of the conjunctival stroma. Mitomycin-C selectively inhibits DNA synthesis and is cell cycle-nonspecific. Consequently, the rapid cycling tumor cells are treated, while the slow cycling stem cells are probably left unaffected. Second, topical mitomycin C can treat satellite and multifocal lesions and the entire ocular surface, obviating the need to establish the margins of excision. [3]

Topical mitomycin 0.4 mg / ml (0.04%) is administered four times a day for three weeks. [4] It has been used successfully as adjunctive therapy for controlling conjunctival and corneal squamous cell carcinoma (SCC) even in extensive recurrent disease. It has been used solely in a concentration of 0.04%. [5]

Mitomycin C in pterygium surgery

The pterygium is a horizontally oriented, triangular growth of abnormal tissue that invades the cornea from a base in the canthal region of the bulbar conjunctiva. Adjunctive use of Mitomycin C in pterygium surgery is reported to be a safe and effective procedure (0.2 - 0.4 mg / ml applied intraoperatively over bare sclera for 1 - 5 minutes)

Among the most impressive results with pterygium were a double-masked, prospective trial [6] using doses of 0.4 mg / ml (0.04%) and 1 mg / ml four times daily for two weeks; they showed a recurrence rate of 2.2%, compared with the placebo rate of 88.9% after five months of follow-up. The weaker dose of mitomycin C had fewer side effects, with equal efficacy.

Other reports also describe good results with no serious complications using 0.2 mg / ml of mitomycin C. [7]

A detailed report of 10 cases with serious, vision-threatening complications associated with mitomycin C use after pterygium surgery has been published [8] when a concentration of 0.4 mg / ml was used postoperatively for up to three weeks. The complications included iritis (eight patients), severe secondary glaucoma (four patients), corneal edema (three patients), corectopia (two patients), sudden-onset mature cataracts (two patients), scleral calcification (one patient), and corneal perforation (one patient).

Mitomycin C in dacryocystorhinostomy

Scarring and fibrous tissue growth over the sewn flaps and osteotomy site is a major cause of DCR failure. From a past study, the most frequent cause of postoperative failure is the fibrous obstruction of common canaliculus and the osteotomy site. [9] In DCR surgery, Mitomycin C is used over the osteotomy site and anastomosed flaps, to suppress fibrous proliferation and scar formation. Intraoperative MMC is effective in maintaining a larger osteotomy size. This modification may possibly improve the success rates over the traditional DCR procedures. [10] A dose ranging from 0.02 to 0.04% applied for a duration of 5 to 30 minutes is effective.

Mitomycin C in squint surgery

Ocular motility dysfunction following ocular surgery can result from postoperative scarring and adhesions. The intraoperative application of mitomycin C is a safe and effective adjunct to surgery in the treatment of restrictive strabismus. [11] Mitomycin C when applied intraoperatively (0.2 mg / ml for 5 minutes) helps in reducing postoperative adhesions following strabismus surgery.

Mitomycin C in refractive surgeries

Photorefractive Keratotomy (PRK) in high myopia remains a challenge due to its complications of haze and regression reported in previous experiments, and also the success rate of laser-assisted in situ keratomileusis (LASIK) in these patients. [12] Using mitomycin-C in PRK for myopia greater than - 5.00 D seems safe and effective, and can reduce haze formation after surgery; therefore, it can be considered a suitable alternative for patients with myopia greater than - 5.00 D, whose corneas lack an appropriate thickness to perform LASIK, with a desirable optical zone. With this method, vision can be corrected with a better quality of vision regarding contrast sensitivity.

Mitomycin C in allergic conjunctivitis

Sodhi PK et al. [13] concluded in their study that topical MMC (0.2 mg / 10 ml) four times a day for three months is a safe and effective alternative to topical azelastine, in treating allergic conjunctivitis.

Complications of mitomycin C

Minor complications:

Ocular pain

Photophobia

Lacrimation

Lid edema

Foreign body sensation (secondary to superficial punctate keratitis)

Major complications: Rare

Scleral ulceration

Necrotizing scleritis

Perforation

Uveitis

Cataract

Glaucoma

Symblepharon formation

Contraindications for topical use

One-eyed patients

Very old patients

Pregnant women

Those with predisposing condition to corneal ulceration or poor healing such as immunocompromised patients or patients with Sjogren's syndrome, atopic keratoconjunctivitis, acne rosacea or herpetic keratitis.

Conclusion

The dose and duration of application of Mitomycin C is still controversial. Randomized trials with longer follow-ups are needed to further establish the safety and efficacy of this drug.